Prolonged treatment of experimental animals with exogenous estrogens including the steroid hormones--estrone, estradiol and estriol--has been reported to induce tumors of the testes, endometrium ovary, cervix and lymphoid tissues, mammary tissue, adrenal cortex, kidney, and anterior pituitary gland. Synthetic estrogens such as DES have also been found to increase the number of tumors in the same tissues in experimental animals.
The exact mechanism of tumor induction by these hormones is unknown. It has even been stated that the role of estrogens on the etiology of breast cancer and other gynecologic cancers may be permissive rather than causative. However, the ultimate question is, "Does the administration of estrogens under certain conditions, in certain dosages and for a certain length of time increase the incidence of neoplasms in responsive tissues?" [Hertz, Cancer, 38, 534 (1976)]. Various epidemiological studies indicate, without proving, that use of estrogen by post-menopausal women is associated with an increased risk of endometrial cancer [Goodman & Gilman-The Pharmacological Basis of Therapeutics, 6th Ed.--pp. 1426, 1429-30 (McMillan, New York 1980)].
It has been proposed, however, that the ring A polyhydroxylated estrogens, the primary products of estradiol or estrone metabolism, although almost devoid of estrogenic activity themselves, could be responsible for the carcinogenic or carcinopromoting action of estradiol. These polyhydroxy metabolites, 2- and 4-hydroxyestradiol or 2- and 4-hydroxyestrone, (catechols or ortho-dihydroxybenzenes) are the major biotransformatory products of estradiol in most species and are known to bind covalently in vitro to protein or peptides and to DNA. Such binding to protein can be suppressed by prior methylation of the catechol.
If oxidation of the phenolic ring of an estrogen is indeed a necessary step in the chain of events leading to increased numbers of tumors in experimental animals, then interference with metabolic oxidations might inhibit cancer induction by estrogens. Following this hypothesis, Li and Li, Proc. 72nd Annual Meeting Am. Assoc. Can. Res., 22, 11 (1981), were able to inhibit diethylstilbestrolinduced renal carcinoma in Syrian hamsters by chronic administration of inhibitors of microsomal cytochrome P-450 enzymes (oxidation enzymes). Another potential approach to prevention of carcinogenesis induction by estrogens would be to modify the estrogen structure so as to prevent oxidation to a catechol. Krey et al., Catechol Estrogens, Ed-Merriam & Lipsett, pages 249-263, (Raven Press, N.Y. 1983), investigating sexual behavior, such as loridosis, in female rats, found that there is reduced catechol estrogen formation with 2-fluoroestradiol and 4-fluoroestradiol--see FIG. 1, page 260. The authors conclude that catechol estrogen formation is not necessary for lordosis. Catechol estrogens had been shown to be precursors for reactive intermediates possibly responsible for tissue injury--Nelson et al., Biochem. Biophys. Res. Comm., 70, 1157 (1976).
The tumorigenicity of dibenzo(a,i)pyrene has been reduced by fluorination at 2,3 and/or 10. It is postulated that oxidation of the hydrocarbon ring to a catechol may be involved in tumor production by this compound.
There is apparently a genetic predisposition to cancer of estrogen dependent tissues in human females. The risk of breast cancer, where there is a family history of such tumor in first degree relatives, is increased 2-3 times [CMA Journal, 121, 505-8 (1979)]. With such persons, the increased risk of cancer potentially induced by administration of estrogen for treatment of estrogen-deficiency states weighs heavily against such estrogen replacement therapy. Stated in somewhat simpler terms, a human female with a history of greater than normal cancers of the breast, cervix, uterus or ovaries in her female relatives will, in many instances, have to endure the menopause rather than to be able to alleviate hot flashes and other menopausal symptoms by taking an estrogen, all for fear of incurring cancer. It is to such a group of human females, those with a genetic predisposition to cancer of estrogen sensitive tissues, that this invention is particularly directed.
It is thus an object of this invention to provide an estrogen of decreased cancer induction potential for use in treating menopause or other estrogen deficiency state in human females.